It is well known to those skilled in the art that the blood levels of drugs need to be maintained above a minimum effective level and below its minimum toxic level in order to obtain the desired therapeutic effects and to minimize side effects. Unfortunately, the pharmacokinetic properties (absorption, elimination and metabolism) of most drugs are such that they need to be administered three to four times a day. This kind of a dosing regimen is very inconvenient and leads to reduction in patient compliance. Reduction of dosing regimen from three times a day (t.i.d.) to twice daily (b.i.d.) to once a day results in increased convenience and comfort and therefore increased patient compliance. Drugs that are administered in the form of conventional tablets of capsules become available to body fluids at a rate that is initially very high, followed by a rapid decline. For many drugs, this delivery pattern results in a transient overdose, followed by a long period of under dosing. This is a pattern of limited clinical usefulness. The delivery pattern was improved in the 1970's with the introduction of a variety of modified delivery systems. Modified release formulations, which are effective in maintaining the therapeutic blood levels over, extended periods of time result in optimal therapy. They not only reduce the frequency of dosing, but they also reduce the severity and frequency of side effects, as they maintain substantially constant blood levels and avoid the fluctuations associated with the conventional immediate release formulations administered three to four times a day.
There are a number of different modified release dosage forms available commercially. However, some of these are expensive to manufacture and can be difficult to swallow, particularly in elderly patients. Many of these modified delivery systems utilize hydrophilic, polymeric matrices that provide useful levels of control to the delivery of sparingly soluble drugs. For soluble drugs, however, and particularly for highly soluble drugs, such matrices do not provide adequate control over the release rate, instead resulting in a release that approximates first-order kinetics and may have a problem of dose dumping or burst release. However, since many modified release dosage forms contain comparatively large amounts of active ingredient it is often necessary to include large amounts of suitable excipients to achieve appropriate controlled release profiles. Clearly, this will tend to increase the size of the dosage form.
The various techniques to make modified release dosage form of drugs as described in prior art are as follows—
One method of prolonging the release of a highly water-soluble drug is disclosed PCT Patent application no. WO99/47128. A biphasic controlled release delivery system for metformin hydrochloride, which has prolonged gastric residence and that swells following hydration. The ratio of inner solid phase to outer continuous phase is 0.5:1 to about 4:1. The major limitation of this invention is that it provides a very bulky formulation for higher doses of the metformin hydrochloride that is very inconvenient for human consumption. For instance, example cited provides formulation of 500 mg metformin hydrochloride with tablet weight of 1.0 gm. Hence restricting to the low dose sustained release tablets of 500 mg or slightly more and making it obligatory to take two tablets of 500 mg each time to provide sustain action. The cited example teaches use of combination of atleast one hydrophilic polymer and which is a essential part for swelling. Non swellable or nonerodeble formulations are not included in the invention.
PCT application No. WO 02/28181 A1 describes a monolithic sustained release formulation of metformin hydrochloride. The method of making the formulation involves hot melt granulation followed by wet granulation with binders or extrusion. The formulation essentially requires binder and auxiliary pharmaceutically acceptable excipients. The formulation consists of metformin hydrochloride polymer and or hydrophobic material. The dosage form release more than 90% of the drug within 8 hours.
Similarly U.S. Pat. No. 6,340,475 B2 assigned to Depomed Inc. describes monolithic controlled release formulation of highly water soluble drugs including metformin hydrochloride. The formulation swells when ingested thus prolonging its residence time in the stomach. The formulations are made of hydrophilic polymers, which results in swellable and erodible matrix.
Another method of prolonging the release of a highly water-soluble drug is disclosed in International Patent application publication no. WO 96/26718, published Sep. 6, 1996. The method of this publication is the incorporation of the drug into a polymeric matrix to form a tablet that is administered orally. The polymer is water-swellable yet erodible in gastric fluids.
Similarly Chih-Ming Chen in international patent application number WO 02/36100 describes a once a formulation of metformin hydrochloride which is based on osmotically controlled technique and that is non expandable in nature and has a passage in the coating membrane for release of drug.
Kim et al. in U.S. Pat. No. 6,337,091 describes a matrix based controlled release formulation for highly soluble drugs over long periods of time. The release controlling agent is a swellable gum which encapsulates or make granules of drug, which is then disposed in more swellable erodible polymers such as HPMC or poly(ethyleneoxide).
These systems can provide for modified release for selected active ingredients like active ingredients with low dose or low water solubility. However, when a highly soluble or high dose active ingredient is used, most of these systems have the disadvantages such as comparatively low payload of active ingredient thus making dosage form bulky and expensive or lead to burst effect or prolonged release of active ingredient for a shorter duration or use of complex manufacturing procedure and/or equipment.
There exists a need for compositions and process for making orally deliverable dosage form containing highly soluble active ingredient as modified release that overcomes the problems discussed above. This invention addresses the need.
Therefore, it would be of considerable clinical benefit to design a dosage form with high pay load of highly soluble active ingredient that would be much easier for the patient to swallow. This type of technology could also be used to reduce the size of many existing drug formulations.
Therefore an object of the present invention is a modified release dosage form of high solubility active ingredient.
The second object of the present invention is a modified release dosage form with high payload of active ingredient, which is suitable for swallowing for humans.
Yet another object of the present invention is to provide a dosage form, which uses dual retard technique to control the release of the high solubility active ingredient and significantly reduce the amount of release controlling agents which are otherwise required in very high quantity and make the dosage form very bulky and therefore pose difficulty in swallowing.
A further object of the present invention is to provide a dosage form, which gives accurate dosing and is simple to prepare.
A further object of the present invention is to provide a dosage form, which can be given twice a day or more preferably can be given once a day.
A further object of the present invention is to provide a dosage form, which can optionally comprise additionally another active ingredient as an immediate release form or modified release form.